In spite of considerable effort by the scientific and healthcare professions to understand and successfully treat obesity, its incidence continues to rise and the obesity-related costs to society are staggering. The enormity of the problem is reflected in recent surveys and goals of the World Health Organization and the National Institutes of Health. Two factors have come to light in recent years that shed light on fundamental aspects of the problem and may hold a key for future therapies. The first factor is that the body possesses a remarkably efficient regulatory system that works to maintain a particular amount of fat in the body. This amount of fat may vary in different environments, and it certainly varies considerably among individuals. Nonetheless, in a constant environment, individuals rigorously defend a particular amount of total stored energy in the form of fat. The second major factor concerning human obesity is that when a diet with a high saturated fat content is consumed on a regular basis, the amount of stored fat that the body defends increases. Hence, epidemiological studies have identified a significant correlation between average dietary fat intake and the incidence of obesity and its related complications mad risk factors among nations. And when the average amount of fat in the diet increases over time, as has occurred in many nations over the past thirty years, the incidence of obesity also increases. The key point is that when individuals are exposed, on a chronic basis, to a higher average level of dietary saturated fat, the otherwise incredibly robust negative feedback system that regulates body fat slips. More fat is stored and the individual moves toward obesity. It is the interaction of these two factors that is the subject of this proposal. More specifically, over three interrelated projects, we ask how consumption of a high saturated fat diet modifies a number of critical factors that determine body fat and the predisposition to become diabetic. Project 1 focuses on how the gut and CNS protein Apo A-IV regulate food intake and can be altered by diets with different amounts and types of fat. Project 2 tests several hypotheses about how saturated versus monounsaturated fats influence the adaptation of the pancreatic beta-cell to increasing insulin resistance. Project 3 seeks to elucidate the mechanisms in the CNS that contribute to the defense of increased body fat that occurs on high saturated fat diet.